Low doses of psychostimulants, including methylphenidate (MPH/Ritalin), are widely used clinically due to their behavioral-calming and cognition-enhancing actions. Less well-recognized is the fact that these drugs exert similar actions in both normal human and animal subjects. Of particular relevance to the proposed studies are the well-documented facilitatory actions of low- doses of MPH and other psychostimulants on prefrontal cortex (PFC)-dependent cognition (i.e. working memory and sustained attention). Despite these cognition-enhancing actions, these drugs possess certain risks, including toxicity and abuse/addiction. For this reason, there is much concern about the widespread use of these drugs, particularly in children. Moreover, these risks preclude use of these drugs in other disorders/conditions associated with relatively modest impairment in PFC- dependent cognition (i.e. normal aging, sleep deprivation). To better develop non-stimulant drugs for the treatment of ADHD and other disorders and conditions associated with impaired PFC- dependent cognition, it is important to understand the neural mechanisms responsible for the cognition-enhancing actions of low-dose psychostimulants. Surprisingly, little is known about the neural substrates underlying the behavioral/cognitive actions of low-dose stimulants. We recently demonstrated that at low doses that improve both working memory and sustained attention in rats, PFC catecholamine efflux displays a greater sensitivity than catecholamine efflux in a number of cortical and subcortical regions outside the PFC. Additional studies indicate that cognition-enhancing doses of MPH increase PFC neuronal responsivity, an effect not observed in the somatosensory cortex. Combined, these observations suggest a prominent role of the PFC in the cognition-enhancing actions of low-dose MPH. The proposed studies are designed to further test this hypothesis and to provide insight into the neural mechanisms that underlie these actions. These studies will use a combination of microdialysis measures of catecholamine release, electrophysiological measurement of PFC neuronal activity, pharmacological manipulations and tests PFC-dependent cognition. These studies will provide novel insight into the neurobiological mechanisms through which low-dose psychostimulants improve cognitive function. Additionally, these studies will provide important information for the development of new pharmacological treatments for ADHD and other disorders/conditions associated with PFC dysfunction. These studies will provide novel insight into the neural mechanisms that underlie the cognition- enhancing actions of low-dose psychostimulants as well as the neurobiology of higher cognitive function. Importantly, these studies will provide information necessary for the development of new pharmacological treatments lacking the potential adverse actions of psychostimulants for a variety of cognitive/behavioral disorders associated with prefrontal cortical dysfunction.